Search for the target genes involved in the suppression of antibody production by TCDD in C57BL/6 mice

Nagai, Haruko; Takei, Teiji; Tohyama, Chiharu; Kubo, Masato; Ryo, Akihide; Nohara, Keiko

doi:10.1016/j.intimp.2004.10.001

Cited by 12 publications

(5 citation statements)

References 48 publications

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“…8, the level of expression of CYP1A1 mRNA in the thymus of the Tg mice was slightly higher than its level of expression in wild-type mice exposed to a single dose of 20 g/kg TCDD. CYP1A1 expression in the spleen of the Tg mice was less than in wild-type mice exposed to 20 g/kg TCDD, which seems plausible because only T cells express CYP1A1 mRNA in the spleen of Tg mice, whereas both T and B cells express CYP1A1 mRNA in TCDD-exposed wild-type mice (43). These results show that the function of the activated AhR in line A heterozygous mice and AhR activated by 20 g/kg TCDD are roughly comparable.…”

Section: Ca-ahr Suppresses the Increase In Spleen Weight And Splenocymentioning

confidence: 69%

Constitutively Active Aryl Hydrocarbon Receptor Expressed Specifically in T-Lineage Cells Causes Thymus Involution and Suppresses the Immunization-Induced Increase in Splenocytes

Nohara

Pan

Tsukumo

et al. 2005

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix-PER-ARNT-SIM superfamily. Xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, bind the receptor and trigger diverse biological reactions. Thymocyte development and T cell-dependent immune reactions are sensitive targets of AhR-dependent 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity. However, the exact role of the AhR in T cells in animals exposed to exogenous ligands has not been clarified because indirect effects of activated AhR in other cell types cannot be excluded. In this study, we generated transgenic (Tg) mice expressing a constitutively active mutant of AhR under the regulation of a T cell-specific CD2 promoter to examine AhR function in T cells. The mRNAs of the constitutively active mutant of AhR and an AhR-induced gene, CYP1A1, were expressed in the thymus and spleen of the Tg mice. The transgene expression was clearly detected in the thymocytes, CD4, and CD8 T cells, but not in the B cells or thymus stromal cells. These Tg mice had a decreased number of thymocytes and an increased percentage of CD8 single-positive thymocytes, but their splenocytes were much less affected. By contrast, the increase in number of T cells and B cells taking place in the spleen after immunization was significantly suppressed in the Tg mice. These results clearly show that AhR activation in the T-lineage cells is directly involved in thymocyte loss and skewed differentiation. They also indicate that AhR activation in T cells and not in B cells suppresses the immunization-induced increase in both T cells and B cells.

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Section: Ca-ahr Suppresses the Increase In Spleen Weight And Splenocymentioning

confidence: 69%

Constitutively Active Aryl Hydrocarbon Receptor Expressed Specifically in T-Lineage Cells Causes Thymus Involution and Suppresses the Immunization-Induced Increase in Splenocytes

Nohara

Pan

Tsukumo

et al. 2005

The Journal of Immunology

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“…In other experimental systems, AhR activation alters the expression of several immunoregulatory genes, and putative AhRE have been identified in the enhancer/promoter regions of a handful of cytokine genes [114–117]. However, a cause-and-effect relationship between possible AhR-mediated changes in gene expression and immune function has yet to be made.…”

Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor is a modulator of anti-viral immunity

Head

Lawrence

2009

Biochemical Pharmacology

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Although immune modulation by AhR ligands has been studied for many years, the impact of AhR activation on host defenses against viral infection has not, until recently, garnered much attention. The development of novel reagents and model systems, new information regarding antiviral immunity, and a growing appreciation for the global health threat posed by viruses have invigorated interest in understanding how environmental signals affect susceptibility to and pathological consequences of viral infection. Using influenza A virus as a model of respiratory viral infection, recent studies show that AhR activation cues signaling events in both leukocytes and non-immune cells. Functional alterations include suppressed lymphocyte responses and increased inflammation in the infected lung. AhR-mediated events within and extrinsic to hematopoietic cells has been investigated using bone marrow chimeras, which show that AhR alters different elements of the immune response by affecting different tissue targets. In particular, suppressed CD8 + T cell responses are due to deregulated events within leukocytes themselves, whereas increased neutrophil recruitment to and IFN-γ levels in the lung result from AhR-regulated events extrinsic to bone marrow-derived cells. This latter discovery suggests that epithelial and endothelial cells are overlooked targets of AhR-mediated changes in immune function. Further support that AhR influences host cell responses to viral infection are provided by several studies demonstrating that AhR interacts directly with viral proteins and affects viral latency. While AhR clearly modulates host responses to viral infection, we still have much to understand about the complex interactions between immune cells, viruses, and the host environment.

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“…B lymphocytes are specialized cells of adaptive immunity that are characterized by the production and secretion of Igs or antibodies (Lebien and Tedder 2008). TCDD has been found to impair B cell activation and function, mainly affecting IgM levels, by different mechanisms related to AHR activity (Nagai et al 2005;Kinoshita et al 2006;Henseler et al 2009;Lu et al 2010;Zhang et al 2013;Phadnis-Moghe et al 2015, 2016Kovalova et al 2017;Dornbos et al 2016Dornbos et al , 2018Zhou, Zhang, et al 2018). In B cells, TCDD has been reported to induce CYP1A1 (Nagai et al 2005) and to impair the expression of different intracellular proteins like the SHP-1, the BCL-6, the Blimp-1, the LCK, and the PAI2, as shown in Figure 4 (Zhang et al 2013;Phadnis-Moghe et al 2015, 2016Dornbos et al 2018;Zhou, Zhang, et al 2018).…”

Section: Ahr Mechanistic Pathway In B Cellsmentioning

confidence: 99%

“…TCDD has been found to impair B cell activation and function, mainly affecting IgM levels, by different mechanisms related to AHR activity (Nagai et al 2005;Kinoshita et al 2006;Henseler et al 2009;Lu et al 2010;Zhang et al 2013;Phadnis-Moghe et al 2015, 2016Kovalova et al 2017;Dornbos et al 2016Dornbos et al , 2018Zhou, Zhang, et al 2018). In B cells, TCDD has been reported to induce CYP1A1 (Nagai et al 2005) and to impair the expression of different intracellular proteins like the SHP-1, the BCL-6, the Blimp-1, the LCK, and the PAI2, as shown in Figure 4 (Zhang et al 2013;Phadnis-Moghe et al 2015, 2016Dornbos et al 2018;Zhou, Zhang, et al 2018). For instance, increased levels of the repressor SHP-1 following TCDD exposure have been reported (Figure 4(A)), resulting in the inhibition of Lyn, Syk, and Btk kinases downstream of BCR, thereby keeping BCR activation at a minimum.…”

Section: Ahr Mechanistic Pathway In B Cellsmentioning

confidence: 99%

EDC-induced mechanisms of immunotoxicity: a systematic review

Vidal

Deepika

Schuhmacher

et al. 2021

Critical Reviews in Toxicology

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Endocrine-disrupting chemicals (EDCs) refer to a group of chemicals that cause adverse effects in human health, impairing hormone production and regulation, resulting in alteration of homeostasis, reproductive, and developmental, and immune system impairments. The immunotoxicity of EDCs involves many mechanisms altering gene expression that depend on the activation of nuclear receptors such as the aryl hydrocarbon receptor (AHR), the estrogen receptor (ER), and the peroxisome proliferator-activated receptor (PPAR), which also results in skin and intestinal disorders, microbiota alterations and inflammatory diseases. This systematic review aims to review different mechanisms of immunotoxicity and immunomodulation of T cells, focusing on T regulatory (Treg) and Th17 subsets, B cells, and dendritic cells (DCs) caused by specific EDCs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), bisphenols (BPs) and polyfluoroalkyl substances (PFASs). To achieve this objective, a systematic study was conducted searching various databases including PubMed and Scopus to find in-vitro, in-vivo, and biomonitoring studies that examine EDC-dependent mechanisms of immunotoxicity. While doing the systematic review, we found species-and cell-specific outcomes and a translational gap between in-vitro and in-vivo experiments. Finally, an adverse outcome pathway (AOP) framework is proposed, which explains mechanistically toxicity endpoints emerging from different EDCs having similar key events and can help to improve our understanding of EDCs mechanisms of immunotoxicity. In conclusion, this review provides insights into the mechanisms of immunotoxicity mediated by EDCs and will help to improve human health risk assessment.

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Search for the target genes involved in the suppression of antibody production by TCDD in C57BL/6 mice

Cited by 12 publications

References 48 publications

Constitutively Active Aryl Hydrocarbon Receptor Expressed Specifically in T-Lineage Cells Causes Thymus Involution and Suppresses the Immunization-Induced Increase in Splenocytes

Constitutively Active Aryl Hydrocarbon Receptor Expressed Specifically in T-Lineage Cells Causes Thymus Involution and Suppresses the Immunization-Induced Increase in Splenocytes

The aryl hydrocarbon receptor is a modulator of anti-viral immunity

EDC-induced mechanisms of immunotoxicity: a systematic review

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